Mutation of the INI1 gene in composite rhabdoid tumor of the endometrium

Summary

Composite rhabdoid tumors are typically adult tumors that contain a component of rhabdoid cells, which are characteristic of the aggressive childhood malignant rhabdoid tumor. Pediatric rhabdoid tumors are characterized by the inactivation of the hSNF5/INI1/SMARCB1 gene, with subsequent loss of expression of the protein. In contrast, only a single composite rhabdoid tumor has demonstrated involvement of the INI1 gene. In our study, INI1 protein expression was studied in 2 uterine carcinosarcomas with rhabdoid components (composite rhabdoid tumors). The rhabdoid component of 1 tumor showed lack of immunoreactivity for the INI1 protein and strong positivity for cyclin D1, whereas the adenocarcinomatous component of the tumor and both components of the second tumor were immunoreactive for the INI1 protein and negative for cyclin D1. Loss of one INI1 allele and a mutation in exon 7 of the remaining allele were detected in the first tumor, consistent with the immunohistochemistry results. Our results demonstrate that deletions and mutations of the INI1 gene can occur also in rare composite rhabdoid tumors of adulthood. Further studies are necessary, however, to determine the prognostic significance of this finding.

Introduction

The INI1/SNF5/SMARCB1 gene at chromosomal band 22q11.2 encodes a member of the SWI/SNF chromatin remodeling complex. This complex is a negative regulator of the cell cycle, modulates cytoskeleton organization, and functions as a tumor suppressor gene [1], [2], [3], [4], [5], [6]. Homozygous deletion of both alleles of the INI1 gene or deletion of one allele and mutation of the second allele results in the development of rhabdoid tumors of the kidney, central nervous system, soft tissue, or liver in infants and young children [2], [6], [7], [8], [9]. Most mutations are single-base-pair, nonsense mutations, and frameshifts that introduce a novel stop codon, and predict a prematurely truncated protein [9]. In practice however, the INI1 protein is not detectable, and a virtually diagnostic feature of these pediatric rhabdoid tumors is their lack of immunoreactivity with monoclonal antibodies against the INI1 protein [10], [11], [12].

Tumors that are morphologically similar to pediatric rhabdoid tumors can also develop in adult patients, often in tumors of diverse histogenesis (carcinomas, sarcomas, melanomas, gliomas, meningiomas) [13], [14], [15], [16], [17], [18], [19], [20], [21]. These tumors, in contrast to pediatric rhabdoid tumors, typically retain the INI1 gene, and are immunoreactive with antibodies to BAF47 [22]. The molecular pathogenesis of these tumors is not known. Neither deletion nor mutation of the INI1 gene was present in a disseminated uterine rhabdoid tumor that was likely of endometrial origin [15]. In a recent study of 40 composite rhabdoid tumors, most of them arising in adult patients, loss of immunoreactivity for the INI1 protein was found only in a single tumor, a rhabdoid component of a leiomyosarcoma [22]. For technical reasons, it was not possible to determine whether the INI1 gene was mutated, but no deletion of 22q was detected in the tumor by fluorescence in situ hybridization with a probe to the BCR gene, which is proximal to INI1 within 22q11.2 [21], [22].

We present a case of endometrial composite rhabdoid tumor with deletion of one copy of the INI1 gene, mutation of the second allele, and lack of immunoreactivity with the BAF47 antibody, the features typical for rhabdoid tumors. In contrast, the second endometrial tumor was immunopositive with antibody BAF47 and, thus, has presumptively a distinct molecular etiology.